Determining cell-specific mechanisms that drive aberrant bone regeneration in Down syndrome

项目总结 这一新的R01应用程序的标题为“确定驱动异常骨再生的细胞特异性机制” 综合征“的重点是确定驱动骨骼中特定年龄和性别缺陷的机制和细胞变化 利用多个唐氏综合征(DS)小鼠模型进行骨再生和挽救骨再生。所有个人 DS表现出显著的骨骼缺陷，即身材矮小和头面部异常，总体上表现为 性二态和多变谱的低骨密度(BMD)使这一弱势群体易患 骨骼受伤。值得注意的是，男性DS患者表现出比DS更早的发病和更大的低BMD倾向 女性。最近使用DS小鼠模型(Dp16和Ts65Dn小鼠)来平行变异性和性行为的研究 在DS患者中观察到的二相性低骨密度表明，雄性DS小鼠骨折愈合严重受损， 雌性Dp16小鼠，而Ts65Dn雌性小鼠愈合骨折的速度与野生型对照组相似。这些发现 展示DS小鼠的低骨密度如何转化为损伤环境，如果在人类身上重述的话 对这一高危群体的深远影响，特别是随着他们年龄的增长。了解中国人复杂的骨愈合表型 DS，这个项目利用了哺乳动物的骨再生模型，截断指尖，末端指骨(P3)，作为 以及具有不同骨积累机制的多种DS小鼠模型(Dp16和Ts65Dn小鼠) 这概括了在DS患者中观察到的性二型低骨密度表型。目标1的研究将建立一个 在急性P3骨损伤反应的背景下，扩展和高分辨率DS转录组数据库，以及 在多种DS小鼠模型中研究破骨细胞和成骨细胞在骨再生过程中的募集和活性。 AIM 2的研究将把性二相DS相关的影响与与年龄有关的性二相影响分开 论破骨细胞和成骨细胞在骨再生中的作用。目标3将确定骨合成代谢剂的能力 (甲状旁腺激素和抗硬化素抗体)挽救DS小鼠的骨再生。这一项目的成功完成将 为开发针对性别和年龄的微调疗法提供基础，以减轻骨质疏松症的后果 在DS患者中治愈。

PROJECT SUMMARY This new R01 application entitled “Determining cell-specific mechanisms that drive aberrant bone regeneration in Down syndrome” is focused on identifying the mechanistic and cellular changes that drive age-and-sex-specific deficits in skeletal regeneration as well as rescuing bone regeneration using multiple murine models of Down syndrome (DS). All individuals with DS exhibit hallmark skeletal defects, i.e. short stature and craniofacial abnormalities, and collectively present with a sexually dimorphic and variable spectrum of low bone mineral density (BMD) that predisposes this vulnerable group to skeletal injuries. Remarkably, male DS patients display an earlier onset and greater propensity for low BMD than DS females. Recent studies using murine models of DS (Dp16 and Ts65Dn mice) to parallel both the variability and the sexually dimorphic low BMD observed in DS patients, have shown that fracture healing is severely impaired in male DS mice and female Dp16 mice, whereas Ts65Dn females heal fractures at a similar rate as wild-type controls. These findings demonstrate how low BMD in DS mice translates to an injury environment that if recapitulated in humans would have profound consequences for this at-risk group, especially as they age. To understand the complex bone healing phenotype in DS, this project utilizes a mammalian model of bone regeneration, amputation of the digit tip, the terminal phalanx (P3), as well as multiple DS murine models (Dp16 and Ts65Dn mice) that possess inherently different mechanisms of bone accrual that recapitulate the sexually dimorphic low BMD phenotype observed in DS patients. Studies in Aim 1 will establish an expansive and high resolution DS transcriptome database in the context of an acute P3 bone injury response, as well as characterize osteoclast and osteoblast recruitment and activity during bone regeneration in multiple murine models of DS. Studies in Aim 2 will decouple the sexually dimorphic DS-related impacts from the sexually dimorphic aged-related impacts on osteoclasts and osteoblasts in the setting of bone regeneration. Aim 3 will determine the capacity for bone anabolic agents (PTH and anti-sclerostin antibody) to rescue bone regeneration in DS mice. The successful completion of this project will provide the foundation for developing fine-tuned sex-and-age-specific therapies to mitigate the consequences of poor bone healing in DS individuals.